Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Memorial Sloan Kettering Cancer Center, New York, USA.
Ann Oncol. 2024 Jul;35(7):643-655. doi: 10.1016/j.annonc.2024.03.009. Epub 2024 May 22.
BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.
背景：聚合酶ε（POLE）和 POLD1 校对缺陷（POLE/D1pd）定义了一种罕见的超突变转移性结直肠癌（mCRC；超过 100 个突变/Mb）亚型。POLE/D1pd mCRC 患者接受免疫检查点抑制剂（ICI）治疗的活性和疗效的特定疾病数据缺乏，并且尚不清楚与接受 ICI 治疗的错配修复缺陷（dMMR）/微卫星不稳定高（MSI-H）mCRC 相比，结局是否不同。 方法：在这项全球研究中，我们收集了 27 例携带导致校对缺陷的 POLE/D1 突变的 mCRC 患者的资料，这些患者单独接受抗程序性细胞死亡配体 1 治疗+/-抗细胞毒性 T 淋巴细胞抗原-4 药物。我们收集了 POLE/D1pd mCRC 患者的临床病理和基因组特征、对 ICI 的反应和生存结局，并与 610 例接受 ICI 治疗的 dMMR/MSI-H mCRC 患者的队列进行了比较。在另一个独立的 7241 例 CRC 队列中进行了进一步的基因组分析，以确定 POLE 和 POLD1pd 分子谱和突变特征。 结果：POLE/D1pd 与较年轻的年龄、男性、较少的 RAS/BRAF 驱动突变以及右侧结肠癌为主有关。与 dMMR/MSI-H mCRC 相比，POLE/D1pd mCRC 患者的总体缓解率（ORR）显著更高（89%对 54%；P=0.01）。在中位随访 24.9 个月（四分位间距：11.3-43.0 个月）后，与 dMMR/MSI-H mCRC 相比，POLE/D1pd 患者的无进展生存期（PFS）显著更长[风险比（HR）0.24，95%置信区间（CI）0.08-0.74，P=0.01]，总生存期（OS）也更长[HR 0.38，95%CI 0.12-1.18，P=0.09]。在包括 DNA 修复缺陷类型的多变量分析中，POLE/D1pd 与显著改善的 PFS（HR 0.17，95%CI 0.04-0.69，P=0.013）和 OS（HR 0.24，95%CI 0.06-0.98，P=0.047）相关。分子谱分析显示，POLE/D1pd 肿瘤具有更高的肿瘤突变负担（TMB）。在两种亚型中均观察到应答，并且与 POLE/D1pd 特征的强度相关。 结论：与 dMMR/MSI-H mCRC 相比，POLE/D1pd mCRC 患者接受 ICI 治疗的肿瘤反应和生存结局更好。
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